Intravenous system for delivering a beneficial agent

ABSTRACT

A formulation chamber is disclosed comprising a wall surrounding a lumen containing a device for delivering a beneficial agent. The chamber has an inlet for admitting a fluid into the chamber and an outlet for letting an agent formulation leave the chamber. The chamber is adapted for use in an intravenous delivery system for delivering an agent formulation to a patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This appln. is a continuation of copending appln. Ser. No. 06/702,292filed Feb. 15, 1985 now U.S. Pat. No. 4,740,198, which appln. Ser. No.06/702,292 is a division of appln. Ser. No. 06/310,047 filed Oct. 8,1981 now U.S. Pat. No. 4,511,353, which appln. 06/310,047 is acontinuation-in-part of appln. Ser. No. 06/283,077 filed Jul. 13, 1981now abandoned.

TECHNICAL FIELD

This invention pertains to an intravenous delivery system, and to a drugformation chamber containing an agent delivery device. The inventionrelates also to a method of administering intravenously an agentformulation, and to a method for forming the agent formulation.

BACKGROUND OF THE INVENTION

The parenteral administration of medical liquids is an establishedclinical practice. The liquids are administered particularlyintravenously, and the practice is used extensively as an integral partof the daily treatment of medical and surgical patients. The liquidscommonly administered include blood and blood substitutes, dextrosesolution, electrolyte solution and saline. Generally the liquids areadministered from an intravenous delivery system having a containersuspended above the patient, with the liquid flowing through a catheterhypodermic needle set to the patient.

The administration of liquids intravenously is a valuable and importantcomponent that contributes to the optimal care of the patient; however,it does not provide a satisfactory means and method for administeringconcomitantly therewith a beneficial agent. Presently, a beneficialagent is administered intravenously by (1) temporarily removing theintravenous system administering the agent to the patient followed byreinserting the intravenous system into the patient; (2) the agent isadded to the liquid in the container and then carried by the flow of theliquid to the patient; (3) agent is added to a liquid in a separatecontainer called a partial fill that is connected to the primaryintravenous line through which line the agent is carried by the flow ofliquid to the patient; (4) agent is contained in a piggyback vial intowhich is introduced an intravenous fluid, with the vial subsequentlyconnected to the primary line through which the agent is administered toa patient, or (5) agent is administered by a pump that exerts a force ona liquid containing agent for intravenously administering the liquidcontaining the agent. While these techniques are used, they have majordisadvantages. For example, they often require preformulation of theagent medication by the hospital pharmacist or nurse, they requireseparate connections for joining the primary intravenous line thatfurther complicates intravenous administration, the use of pumps canproduce pressures that can vary at the delivery site and the pressurecan give rise to thrombosis, and the rate of agent delivery to thepatient often is unknown as it is not rate-controlled agent delivery butdelivery dependent on the flow of fluid administered over time.

In view of this presentation, it is apparent a critical need exists inthe field of intravenous delivery for a rate-controlling means foradministering a beneficial agent in intravenous delivery systems.

DISCLOSURE OF THE INVENTION

Accordingly, a principal object of this invention is to provide anintravenous delivery system comprising means for admitting an agent at arate controlled by the means into an intravenous fluid for optimizingthe care of a human whose prognosis benefits from intravenous delivery.

Another object of the invention is to provide an intravenous deliverysystem comprising an agent formulation chamber comprising an agentdelivery device for admitting an agent at a rate controlled by thedelivery device into an intravenous fluid for optimizing the care of apatient on intravenous delivery.

Another object of the invention is to provide an agent formulationchamber adapted for use with an intravenous delivery system and whichchamber houses an agent delivery device for admitting an agent at a rateessentially controlled by the device into an intravenous fluid admittedinto the chamber.

Another object of the invention is to provide an intravenous therapeuticsystem comprising a container and a drug formulation chamber that housesa device for delivering a drug at a rate governed by the device into amedical fluid that flows from the container into the chamber and then toa drug recipient.

The invention concerns both an intravenous delivery system comprising anagent formulation chamber and the agent formulation chamber. The chambercontains an agent formulation, wherein an agent originally present in adelivery means present in the chamber is released at a rate controlledby the delivery means. The agent on its release is formulated in situwith an intravenous fluid that enters the chamber with the agentreleased at a controlled rate that is essentially independent of thevolume rate of an intravenous fluid entering the formulation chamber,and then infused into a recipient. The expression delivery means, asused herein, generically denotes a means or a system for storing anddelivering a beneficial agent at a rate controlled by the means toestablish a beneficial or a therapeutic need. The means, in presentlypreferred embodiments, are designed and manufactured as an agentdelivery device, which device also is a rate-controlled dosage form ofthe agent. The delivery device or dosage forms stores an amount of agentfor executing a prescribed beneficial program, and it provides for thepreprogrammed, unattended delivery of a beneficially or atherapeutically effective amount of the agent to produce a beneficial ortherapeutic result. The delivery device, or the dosage form, are adaptedfor easy placement and retention in the formulation chamber, and theysubstantially maintain their physical and chemical integrity duringtheir release history. The expression beneficial agent genericallydenotes a substance that produces a beneficial or a therapeutic result,such as a drug, a carbohydrate, and/or the like. The term fluid orliquid denotes a fluid that can be administered parenterally includingintravenously comprising pharmaceutically acceptable fluids that arealso a pharmaceutically acceptable carrier for the agent. The inventionalso is an intravenous therapeutic system for administering a liquiddrug formulation, wherein the liquid drug formulation is formulated insitu. The intravenous delivery system generically comprises incombination:

(a) a container for storing a pharmaceutically acceptable liquid carrierfor the agent;

(b) an agent formulation chamber comprising: an inlet that permitscommunication with the container to let a liquid carrier flow from thecontainer into the formulation chamber; and an outlet through which theliquid exits the chamber;

(c) an agent delivery means in the chamber, which means is arate-controlled dosage form of agent that is in communication with aliquid flowing through the chamber, and wherein when in operation, themeans releases the agent into the liquid at a predetermined rate that issubstantially independent of the volume rate of liquid flow flowingthrough the chamber; and,

(d) a conduit that communicates with the chamber outlet and extends toan infusion recipient site.

The agent formulation chamber generally comprises means for housing anddelivering an agent at a rate-controlled by the means overtime.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale, but are set forth toillustrate various embodiments of the invention, the Figures are asfollows:

FIG. 1 is a perspective view showing an embodiment of the inventioncomprising an intravenous delivery system in use;

FIGS. 2a and 2b are perspective views of an agent formulation chamberprovided by the invention with the formulation chamber housing a meansfor delivering an agent which means is manufactured as an agent deliverydevice;

FIG. 3 is a view of an agent formulation chamber containing an agentdelivery device comprising an agent release rate controlling membranesurrounding a reservoir containing agent;

FIG. 4 is a view of an agent formulation chamber containing a deliverydevice comprising a release rate controlling membrane surrounding adifferent reservoir containing agent;

FIG. 5 is a view of an agent formulation chamber containing a deliverydevice comprising a microporous membrane surrounding a reservoircontaining agent;

FIG. 6 is a view of an agent formulation chamber containing a deliverydevice comprising a matrix containing agent;

FIG. 7 is a view of an agent formulation chamber containing an agentdelivery device comprising a microporous matrix containing an agent;

FIG. 8 is a view of an agent formulation chamber containing a deliverydevice comprising depots of agent;

FIG. 9 is a view of an agent formulation chamber containing a deliverydevice comprising a housing and driving member surrounding a flexiblecontainer;

FIG. 10 is an embodiment of the invention illustrating an agentformulation chamber in fragmentary view;

FIG. 11 is a sectional, fragmentary view of the parts of the embodimentshown in FIG. 10;

FIG. 12 is an enlarged, partly sectional view of another formulationchamber;

FIG. 13 is an enlarged, partly sectional view of still anotherembodiment of an agent formulation chamber housing a delivery device;

FIG. 14 is a graph showing a typical relationship between the mass rateof agent administration and the volume flow rate of intravenous fluid tothe patient that results from use of the invention; and,

FIG. 15 is a graph that indicates the time required for the deliveryrate to reach a steady state of delivery.

In the specification and the drawings, like parts in related Figures areidentified by like numbers. The terms appearing earlier in thespecification and in the description of the drawings are describedhereafter in the disclosure.

MODES FOR CARRYING OUT THE INVENTION

FIG. 1 illustrates an operative embodiment of the invention, comprisingan intravenous delivery system, generally designated by the numeral 10.System 10 comprises a container 12 that contains a liquid 13 adapted forintravenous administration, and an administration set, generallydesignated 14. The liquid 13 in container 12 will typically be a medicalfluid, a sterile solution such as an aqueous solution of dextrose,saline, and electrolytes. It must be a pharmaceutical vehicle forintravenous administration and for an agent that is to be administeredto a recipient. Container 12 is manufactured from glass or plastic, andpreferrably of the no air-tube vacuum type and thus it is used with anadministration set that has an air inlet filter. Other types ofcontainers such as the air-tube vacuum type, or the non-vented type canbe used for the intended purpose. These alternative containers do notrequire an air filter in the administration set. Container 12 can berigid, semi-rigid or flexible in structure, and it is usually adapted tobe hung neck-down from a hanger 15 by a handle or strap 16 that connectsor surrounds container 12. The neck of container 12 is covered by aclosure 17, generally made of rubber and air-tight.

Administration set 14 and container 12 are interconnected by piercingclosure 17 with one end of a needle or hollow spike 18 attached to orformed as a part of administration set 14. Needle 18 is equipped with aside air vent 19. The other end of needle 18 is enlarged and fits snuglyinto a drip chamber 22. Drip chamber 22 traps air contained in the setand facilitates adjusting the flow rate of intravenous fluid 13 fromcontainer 12 as the flow proceeds drop wise. The outlet at the bottom ofdrip chamber 22 is connected to a first segment of tubing 23 which fitsinto inlet 24 of agent formulation chamber 25, the details of which arepresented in subsequent figures. A second segment of tubing 23 connectsto outlet 26 of agent formulation chamber 25 and leads to bacterialfilter 27. A third segment of tubing 23 extends from filter 27 to aninfusion agent receptor site, terminating in an adapter-needle assembly28 that is inserted into a vein of a warm-blooded animal 29, shown as ahuman patient's arm. An affixation means 32, usually a piece of tape,holds adapter-needle assembly 28 firmly in place on the recipient's arm.The administration set can also include a pair of tubing clamps 33 and34 located on either side of formulation chamber 25 that may be used togovern or stop the flow rate of intravenous fluid through theintravenous therapy system.

Agent formulation chamber 25, as seen in FIGS. 2A and 2B, is the uniquecomponent of the intravenous delivery system. Agent formulation chamber25 is sized and adapted for use in intravenous systems, it isself-contained, self-powered and amenable to low cost manufacturing. Theuse of the agent formulation chamber with an agent delivery meanstherein does not require any reconstitution or admixture prior to use.Agent formulation chamber 25, hereafter referred to as chamber 25, inthe illustrated embodiment, comprises a wall 9 that surrounds anddefines an internal space 38. Chamber 25 has an inlet 24 adapted andsized for placing chamber 25 into an intravenous delivery system, and ithas an outlet 26 also adapted and sized for placing the chamber in thesystem. Inlet 24 and outlet 26 are made for receiving tube 23. Chamber25, is manufactured of glass, plastic or the like, and as illustrated itis made of a transparent material for illustrating its structure and adevice housed therein. In the embodiment shown, chamber 25 comprises apair of interfitting housing halves 35 and 36 for containing agentdelivery device 37 within space or lumen 38. A retaining means 8 inhousing 36 permits the passage of fluid, keeps device 37 in lumen 38,and it also prevents device 37 from blocking outlet 26. Agent deliverydevice 37, in the illustrated embodiment is an osmotic, rate-controlledsolid dosage form as described by patentee Felix Theeuwes in U.S. Pat.No. 3,845,770. The osmotic device 37, seen in opened section, comprisesa semipermeable wall, 37a, such as cellulose acylate, cellulosediacylate, cellulose triacylate, cellulose acetate, cellulose diacetateor cellulose triacetate, that surrounds and forms a compartment 37b. Apassageway 37c extends through semipermeable wall 37a and communicatescompartment 37b and the exterior of device 37. Compartment 37b containsan agent formulation 37d, represented by dots, which agent formulationexhibits an osmotic pressure gradient across wall 37a of device 37against an external fluid that enters chamber 25. The agent formulationcan comprise an agent that exhibits an osmotic pressure gradient, or theagent formulation can comprise a drug mixed with an osmoticallyeffective solute, such as sodium chloride, potassium chloride and thelike, that exhibit an osmotic pressure substantially greater than thefluid in the chamber 25. In operation, fluid that enters in the chamber25 is imbibed through the semipermeable wall of the device into thecompartment in a tendency towards osmotic equilibrium at a ratedetermined by the permeability of the wall and the osmotic gradientacross the wall thereby producing a solution that is dispensed throughthe passageway at a rate controlled by the device over a prolongedperiod of time. The delivery of agent formulation 37d for homogenouslyblending with fluid in chamber 25, is controlled by device 37, and itsrate of delivery is independent of the rate of fluid flow, and the pH ofthe fluid in the chamber. Device 37 maintains its physical and chemicalintegrity throughout its releasing history. In other embodiments, notshown, chamber 25 can be manufactured as a one-piece unit with thedelivery device therein, or chamber 25 can be manufactured with aclosable entrance for admitting the delivery device. Additionally,another embodiment of the invention comprises chamber 25 simultaneouslyacting as a drip chamber while housing the agent delivery device. Inthis embodiment the agent formulation chamber-drip chamber is used toachieve a desired fluid drop rate. For example, the agent formulationchamber-drip chamber can have a fast drop rate for adults, or it canhave a slower drop rate for pediatric use. The agent formulation-dripchamber can be made with various sized inlets for controlling the rateof drip, or the drip can be controlled by a regulating clamp on thetubing conveying fluid thereto. The agent formulation chamber-dripchamber can deliver, for example from 2 to 75 drops per milliliter overfrom 1 minute to 1 hour. More preferrably, the therapist can adjust therate of flow of 2 to 20 drops per minute, or for the need of thepatient.

The rate performance of the delivery devices used in formulation chamber25 for the purpose of the invention also can be described mathematicallyin terms of the physical and chemical composition of the agent releasesystems. Generally, delivery systems encompassed by this invention arethose for which Q_(R) ≦0.1Q_(KVO), where Q_(KVO) is the flow of fluidrequired to maintain flow into the veins of an animal in which the flowpath terminates, by needle or catheter. This flow is referred to as the"keep vein open" rate, KVO, and it typically is for an adult patientabout 10-20 drops per minute, or 0.5-1.0 ml per minute. Q_(R) is themaximum rate of fluid flow needed for the delivery system to releaseagent in solution at its label rate. Thus, delivery systems for adultuse require less than 0.05-0.1 ml/min to achieve label delivery rate,and show independence of delivery rate from flow at all higher flows areencompassed by this invention. Delivery systems for pediatric use willhave a lower absolute limit, but still satisfy the general criterion ofQ_(R) ≦0.1Q_(KVO).

During operation of device 37 as seen in FIG. 2B, the mass delivery rateof agent from chamber 25 is given by the volume flow rate F expressed byequation 1, of fluid entering chamber 25, times the concentration ofagent C₂, in the chamber with a volume V₂. In the chamber, V₂ is the

    F=dV/dt                                                    (1)

volume of the total chamber less the volume V₁ of agent delivery device37. In the chamber, it is assumed that lumen V₂ is stirred by fluid flowto achieve a uniform concentration C₂. The chamber is designed toproduce a steady state mass flow rate dm₃ /dt, expressed in equation 2independent of flow rate F leaving the chamber and conveyed to an agentrecipient, represented by volume V₃. The calculations presented here are

    dm.sub.3 /dt=dV/dt.C.sub.2                                 (2)

performed to determine the flow regimen for which the intended endresult can be achieved over time. The calculations are for an osmoticdevice, designated as 37, containing a mass of agent m, at the start ofa beneficial delivery program. During operation, the device delivers ata zero order rate as given by equation (3). ##EQU1## wherein: K₁ is thepermeability of the wall of the delivery device to water, A₁ is the wallarea of the device, h₁ is the thickness of the wall, π₁, is the osmoticpressure of saturated agent solution in the device, π₂ is the osmoticpressure of the solution in the lumen of the chamber at concentrationC₂, and S₁ is the solubility of agent in volume V₁ in the device. Themass of agent m₂ in the lumen of the chamber at concentration C₂ isconveyed to the patient. The patient then has a total amount of agentinfused of mass m₃ such that the mass balance at any time is given byequation 4.

    m.sub.10 =m.sub.1 +m.sub.2 +m.sub.3                        (4)

As a result, the mass change in each compartment, the device, thechamber and the patient, is expressed by equation 5, ##EQU2## wherein

    dm.sub.3 /dt=FC.sub.2                                      (6)

since

    m.sub.2 =V.sub.2.C.sub.2                                   (7)

and it follows that ##EQU3## it follows that

    dm.sub.2 /dt=V.sub.2 dC.sub.2 dt                           (10)

From equations (3), (5), (6) and (10), equation (11) follows:

    V.sub.2 /dtdC.sub.2 =K.sub.1 /h.sub.2 A.sub.1 (π.sub.1 -π.sub.2)S-FC.sub.2                                    (11)

where 2 and C₂ are related through Van Hoff's law as shown by 12:

    2/1=C.sub.2 /S.sub.1                                       (12)

Equations (11) and (12) result in differential equation 13, from whichC₂ follows as a function of time. ##EQU4## and when equation (14) issubstituted therein,

    F=K.sub.1 A.sub.1 /h.sub.1.π.sub.1                      (14)

equations (15) and (16) follow, ##EQU5## and for (16) the solution isgiven by equation (17). ##EQU6## Equation (17) indicates the time coursein which C₂ attains its steady state value. The steady state value isgiven by 18, with the flow rate ##EQU7## The flow rate into the patientis obtained from (17) and (2) as equation (19). ##EQU8## Equation 19leads to (1) the minimum flow rate F_(m) needed to achieve a regimenindependent of flow, and (2) the time it takes until the patientreceives steady state intravenous administration. The steady state flowrate achieved with the infuser is given by equation 20 or 21, ##EQU9##and the maximum steady state flow rate is the steady state expressed byequation 22,

    Z.sub.sm =F.sub.1 S.sub.1                                  (22)

the delivery rate from the delivery device. The steady state flow rateas a function of flow F is given by equation 23 ##EQU10## andgraphically represented in FIG. 14, solid line, as a function of F/F₁,wherein it can be seen at high flow rates F>F₁, the agent delivery ratefrom the device is independent of fluid flow in the chamber.

Generally, the volume flow rates from an osmotic device delivering athigh rates, for example 100 mg/hr, are on the order of 0.05 to 0.2ml/hr. The incoming fluid rate from a container containing a medicalliquid, and referred to as the drip rates from an intravenous gravityfeed system are in the range of from 1 to 400 ml/hr, and for these tworanges the total mass delivery rate is within 80 percent of the designedrate at all times.

The steady state rate of equation (20) can be expressed relative to thenon-steady state rate of equation (19) by equation 24. ##EQU11## Underoperating conditions, FF₁, equation (24) can be expressed as equation(25), and ##EQU12## V₂ /F is a characteristic time of the chamber. It isthe time it takes to clear volume V₂ at incoming flow rate F. Thesesystems are typically designed such that this time is small to reducethe start up time, and the dead volume V₂ in the chamber is smallcompared to the volume transported in the start up time. The dead volumeV₂ is usually less than 1 ml. Thus, for the minimum flow rate of 1 ml/hrused in intravenous therapy, the characteristic time would be one hour.Accompanying FIG. 15 represents the time it takes to achieve anyfraction of a steady state value in units of characteristic time, andgenerally indicating 80 percent of the steady state rate is achieved in1.5 times the characteristic time.

FIG. 3 depicts agent formulation chamber 25, in opened section,containing another device 40 for delivering an agent into anintravenously acceptable fluid that enters chamber 25. Device 40 isillustrated in opened-section and it comprises an inner mass transferconductor 41, illustrated as a solid core and formed of a polymericmaterial such as cured polydimethylisoxane, with agent 42 dispersedtherethrough. Surrounding mass transfer conductor 41 is an agent releaserate controlling membrane 43, preferrably formed of a polymericmaterial, such as polyethylene. Both conductor 41 and membrane 43 arepermeable to the passage of agent 42 by diffusion, that is, agent candissolve in and diffuse through conductor 41 and membrane 43. However,the permeability of conductor 41 is greater than that of membrane 43,and membrane 43 thus acts as the rate controlling member for agentrelease from device 40. Device 40 maintains its physical and chemicalintegrity throughout the period of agent delivery. Agent delivery device40 is disclosed in U.S. Pat. No. 3,845,480.

FIG. 4 illustrates the agent formulation chamber, with a section of itswall removed, housing delivery device 44 for delivering an agent at arate controlled by device 44 into a fluid that enters chamber 25. Device44 is seen in opened-section and it comprises a reservoir 45 formed of aliquid mass transfer conductor 46 such as a medical oil liquid carrier,permeable to the passage of agent, containing agent 47 such as the drugphenobarbital. Reservoir 45 is surrounded by a wall 48 formed of anagent or drug release rate controlling material permeable to the passageof agent 47, such as a polyolefin. The rate of passage of agent 47 islower than the rate of passage through conductor 46, so that agentrelease by wall 48 is the agent release rate controlling step forreleasing agent 47 from device 44. Device 44 maintains its physical andchemical integrity throughout its agent release history. Agent deliverydevice 44 is disclosed in U.S. Pat. No. 3,993,073, which patent isincorporated herein.

FIG. 5 illustrates agent formulation chamber 25, with a part of its wallremoved, housing another device 49 for delivering an agent into a liquidthat enters chamber 25 for forming an intravenously acceptable agentformulation. Device 49 is seen in opened-section and it comprises a wall52 surrounding a reservoir 50 containing agent 51. The reservoir isformed of a solid carrier permeable to the passage of agent such ascured polydimethylsiloxane containing the drug diazepam. Wall 52 isformed of a microporous material, the pores of which contain an agentrelease rate controlling medium permeable to the passage of agent 51,for example, formed of a microporous polymer made by coprecipitation ofa polycation and a polyanion. The release of agent 51 is controlled bydevice 49, which device maintains its physical and chemical integrityduring the period of time it is in chamber 25. Device 49 is disclosed inU.S. Pat. No. 3,993,072, which patent is incorporated herein byreference.

FIG. 6 is a view of formulation chamber 25 having part of its housingremoved and housing device 53 for delivering an agent into a medicalfluid that enters chamber 25 for forming in situ an intravenouslyacceptable agent formulation solution. Device 53 comprises a matrix 54containing agent 55 distributed therethrough. Matrix 55 is formed from apolymeric material that is non-erodible, that is, it keeps its physicaland chemical integrity over time, and it is permeable to the passage ofagent 55 by the process of diffusion. The rate of agent release from thematrix is determined by the rate the agent dissolves in and passesthrough the matrix by diffusion, so that from the matrix it is the agentrelease rate controlling step. The matrix can possess any shape such asrod, disc and the like that fits into chamber 25. The polymers includepolyolefins such as polyethylene containing muscle relaxants and thelike. Materials useful for manufacturing the devices are disclosed inU.S. Pat. No. 3,921,636.

FIG. 7 is a view of agent formulation chamber 25, in opened view,housing device 56 for delivering an agent into a fluid that enterschamber 25. Device 56 is seen in opened section, and it is formed of amicroporous polymeric material 57 containing agent 58 distributedtherethrough. Matrix 57 is formed of a non-toxic, inert polymer, that isnon-erodible and has a plurality of micropores for releasing agent at acontrolled rate to fluid entering chamber 25. Microporous materialsuseful for the present purpose are disclosed in U.S. Pat. Nos. 3,797,494and 3,948,254.

FIG. 8 illustrates agent formulation chamber 25, in opened view, housingdevice 59 for delivering an agent into a medical fluid that enterschamber 25. Device 59 is seen in opened section and it comprises depotsof agent solute 61 dispersed in and surrounded substantiallyindividually by a polymer 60 that is impermeable to the passage of agentsolute and permeable to the passage of fluid that enters chamber 25.Agent or a medication solute 61 exhibits an osmotic pressure gradientacross the polymer against fluid that enters chamber 25. Agent 61 isreleased at a controlled rate by fluid from the chamber being imbibedthrough the polymer into the depots to dissolve the solute and generatea hydrostatic pressure in the depots, which pressure is applied againstthe wall of the depots thereby forming apertures that release the agentat a controlled rate over time. Polymer 60 is non-erodible, and device59 can be shaped as a matrix, a rod, a disc, or like shapes. Proceduresand materials useful for manufacturing osmotic bursting delivery systemsare described in U.S. Pat. No. 4,177,256.

FIG. 9 illustrates agent formulation chamber 25, in opened view,containing device 62 useful for delivering an agent into a medicallyacceptable fluid passing through chamber 25. Device 62 is seen in openedview and it comprises an exterior wall 63 formed of a semipermeablepolymer permeable to fluid and substantially impermeable to the passageof agents and solutes. A layer 64 of an osmotically effective solute,for example sodium chloride, is deposited on the inner surface of wall63. Solute layer 64 surrounds an inner container 65 formed of a flexiblematerial that is impermeable to solute and agent. Container 65 has apassageway 66 for delivering an agent 67 into a fluid in chamber 25.Device 62 dispenses agent by fluid permeating from chamber 25 throughthe outer wall 63 to continuously dissolve solute 64 in a tendencytowards osmotic equilibrium, thereby continuously increasing the volumebetween wall 63 and container 65. This increase causes container 65 tocontinuously collapse and dispense agent 67 from device 62 at acontrolled rate through passageway 66 to fluid passing through chamber25. Osmotically powered agent dispensing devices are disclosed in U.S.Pat. Nos. 3,760,984 and 3,995,631.

In FIGS. 10 and 11 another chamber 25 provided by the invention is seencomposed of a pair of interfitting housing halves 35, 36 and a ratecontrolled solid agent or drug dosage form 37 contained within the lumen38 of chamber 25. The chamber inlet 24 is in this embodiment thecone-shaped of housing half 35, and the chamber outlet 26 is in thecone-shaped end of half 36. The inside perimeter of half 36 has a seriesof downwardly inclined flutes 39 on which dosage form 37 rests. Thedosage form is supported by the flutes above the outlet, and is thuskept from blocking the outlet. Dosage form 37 is an osmotic,rate-controlled dosage form as described above and in U.S. Pat. No.3,845,770, which disclosure is incorporated herein by reference. In theillustrated embodiment, dosage form 37 has passageway 37c oriented inthe direction of fluid flow through chamber 25 for lessening theincidence of membrane polarisation and to produce release ratespractically unaffected by effluent agent. In this operation, the releasepattern is seen in FIG. 14 as represented by the dashed lines. Anotherosmotic agent delivery device, not shown, that can be positioned inchamber 25 is disclosed by patentee Felix Theeuwes in U.S. Pat. No.4,111,202, which patent is incorporated herein by reference. The deviceof this patent comprises a semipermeable wall that surrounds a first andsecond compartment with the first compartment containing an agent andthe second compartment containing an osmotically effective solute thatexhibits an osmotic pressure gradient across the semipermeable wall. Inthis device, the compartments are separated by a flexible membrane, andthe device has a passageway that communicates with the compartmentcontaining the agent for its delivery from the device. This device, whenin operation, delivers agent by imbibing fluid from the infuser into thefirst compartment to form a solution containing agent, and into thesecond compartment to form a solution containing the solute whichcontinuously fill the second compartment and expands the membrane intothe first. The agent is delivered through the passageway by the combinedactions of the first and second compartments at a controlled rate over aperiod of time. For this delivery device, like the device describedabove, the mass rate of agent released by the device is substantiallyindependent of the volume flow of intravenous fluid to the patient as itis instead controlled by the mass release of agent from the dosagedevice. This relationship is shown in FIG. 14, in solid line. In FIG. 14the rate of release from the device when passageway 37c is directed inthe path of liquid flow is illustrated in dashed lines.

Agent administration that is independent of intravenous fluid flow rateis extremely advantageous since careful control of the volume flow rateof intravenous fluid through the formulation chamber is not required.Hence, repeated adjustment of the flow by medical personnel, or the useof expensive, automated flow monitors is not needed. The operation alsohas all the advantages that are associated with the fact that theformulation of agent and intravenous fluid is carried out automaticallyin situ within the chamber. Moreover, since the chamber can bepositioned within the intravenous therapeutic system when needed, theseparation of the agent and the intravenous fluid until administrationprovides significant stability and handling advantages. The presentinvention also eliminates the need to have the agent formulated into aparenteral solution by a pharmacist, and, it also eliminates the needfor the agent to be packaged separately from the intravenous fluidcontainer. Another advantage provided by this invention, is since theagent dosage delivery device is compatible with conventionalsterilization techniques that are commonly used to sterilize intravenoustherapy systems, the agent formulation chamber, including the agentdelivery device, may be incorporated into the entire intravenous systemat the time of manufacture and sterilized therewith.

The invention also provides that agent delivery devices each containingvarious amounts of an agent or an amount of drug can be placed into theformulation chamber. The device can contain from about 1 mg to 5 g ofagent, or more, in for example 1 to 7 or more dosage units. The devicecan release agent at a rate of 10 ng/hr up to 3 g/hr into the chamberhaving a volume capacity of at least 2 ml up to 250 ml, through whichintravenous fluid flows at a rate of 1 ml/hr up to 20 ml/hr or higher.The term drug is represented by heparin, isoproterenol, and the like.

FIG. 12 illustrates another agent formulation chamber designated 25. Inthis chamber, the rate-controlled dosage delivery device is not indirect path of the intravenous fluid flow through chamber 25. In thisembodiment chamber 25 includes a pair of hollow interfitting housinghalves 71 and 73. Housing half 71 has an inlet opening or itscone-shaped end for tubing 23. The inner surface of half 71 carries apair of integral flanges 74 and 76 that together with a thin microporousmembrane 70 define an enclosed pocket 75 inside the lumen 72 of chamber25. An agent delivery device 37 is contained within the pocket. Device37 is, as described above, a complete rate-controlled form and it mayadditionally act in combination with membrane 70 to enhance the controlof agent into passing fluid. Such combinations, in which an element ofchamber is used with a delivery device are intended to be within thephrase rate-controlled delivery as used herein. In such combinations,membrane 70 can serve as a rate-controlling barrier that regulates therate at which the agent enters the mainstream of intravenous fluid flowthrough the chamber. Since device 37 is a complete rate-controlled form,the membrane acts as a supplemental barrier or as a means for confiningthe device so that it does not block the entrance or exit of chamber 25.Membrane 70 pemits the passage of fluid so that as intravenous fluidfills and passes through the chamber, which flow is represented by thestraight arrow in FIG. 12, water from the fluid will diffuse,represented by curved arrows, through the pores of the membrane into thepocket and motivate device 37 to release drug. The released agent willpass from the pocket through the membrane into the mainstream flowthrough chamber 25. The rate at which the agent will enter themainstream will depend on its concentration in the solution within thepocket, the surface area of membrane 70, and the rate of passage of themembrane to agent. In any event, that rate is independent of the overallflow rate of intravenous fluid through chamber 25. Accordingly, theagent is formulated in situ within chamber 25 and it is administered tothe patient at a rate that is dependent upon the characteristics of thedevice. The microporous membrane 70 may be useful also to prevent agentparticles from entering the flow path, and for providing an extra marginof safety against microorganisms, in the event any may have survived thesterilization producedure for the system.

FIG. 13 shows another agent formulation chamber, generally designated25, in which the dosage form is not in the direct path of theintravenous fluid flow through the chamber. The chamber is particularlyadapted to hold a plurality of the same or different delivery devices.The chamber, like those shown in the other figures, includes a pair ofhollow, interfitting housing halves 80 and 81, that have an inletopening and outlet opening, not shown, at their respective ends. Theinside surface of half 80 carries a pair of radial flanges 82 and 83,that extend entirely around the inner circumference of the half. Theseflanges, together with a tubular microporous membrane 84 that isattached at its ends to the flanges, divides the lumen of the chamberinto a main intravenous flow path 85 and an outer concentric pocket 86.A plurality of agent delivery units 37 are contained within the pocket.Membrane 84 and pocket 86 function in the same manner as membrane 70 andpocket 75 of FIG. 12. That is, as intravenous fluid flows through thechamber, water from the fluid diffuses through the membrane into pocket86 and causes the device to release agent. The agent then diffuses fromthe pocket through the membrane and into the mainstream of theintravenous fluid flow. In instances in which the devices are different,it may be desirable to divide pocket 86 into a plurality of pockets, onefor each device. This may be accomplished with impermeable axialpartitions, not shown, that extend between the inner surface of thehalf, the membrane, and the two flanges. In such instances it may bealso desirable to have membrane 84 formed from segments of differentmicroporous materials, each segment covering a separate pocket. In thismanner different release rates of different agents into the passingintravenous fluid may be effected.

This novel invention uses means for the obtainment of precise control ofagent release into an intravenous therapeutic system. While there hasbeen described and pointed out features of the invention as applied topresently preferred embodiments, those skilled in the art willappreciate that various modifications, changes, additions, and omissionsin the system illustrated and described can be made without departingfrom the spirit of the invention.

What is claimed is:
 1. A method for adding a beneficial parenterallyadministrable drug to a parenterally acceptable fluid for forming aparenterally administrable fluid beneficial drug formulation, whichmethod comprises:(a) admitting the parenteral fluid into a formulationchamber, the formulation chamber comprising:(1) a wall surrounding aspace provided with a first and second compartment therein; (2) fluidinlet and outlet means communicating with the first compartment toprovide a flow path; (3) means for permitting fluid to flow from theflow path through the second compartment; (4) a beneficial parenterallyadministrable solid drug in the second compartment; and, (b) adding thebeneficial drug to the fluid by permitting fluid to flow through thesecond compartment, wherein the beneficial drug is added to the fluidthereby forming a parenterally administerable fluid beneficial drugformulation.
 2. The method for adding a beneficial drug to aparenterally acceptable fluid according to claim 1, wherein thebeneficial drug is contained in a means for storing and releasing thebeneficial drug.
 3. The method for adding a beneficial drug to aparenterally acceptable fluid according to claim 1, wherein the drug iscontained in a mass that is microporous.
 4. The method for adding abeneficial drug to a parenterally acceptable fluid according to claim 1,wherein the beneficial drug is contained in a mass transfer conductorfor the drug.
 5. The method for adding a beneficial drug to aparenterally acceptable fluid according to claim 1, wherein thecompartments are separated by a barrier that permits the passage offluid into the second compartment.
 6. The method for adding a beneficialdrug to a parenterally acceptable fluid according to claim 1, whereinthe beneficial drug is added to the fluid to form a solution that passesthrough a membrane that separates the compartments and then enters thefluid flow path that leaves the formulation chamber.
 7. A formulationchamber for use with a parenteral delivery system for formulating aparenterally administrable drug formulation comprising a parenterallyadministrable fluid and a parenterally administrable drug, theformulation chamber comprising:(a) a housing means defining a first andsecond compartment therein; (b) fluid inlet and outlet means forconnecting said housing to a parenteral delivery system, said inlet andoutlet means communicating with the first compartment to provide a flowpath; (c) means for permitting fluid to flow from the flow path into thesecond compartment; (d) a beneficial parenterally administrable soliddrug housed in the second compartment; and (e) wherein, when theformulation chamber is in use with a parenteral delivery system,parenterally administrable fluid enters the formulation chamber andcontacts the parenterally administrable drug for formulating aparenterally administrable drug fluid formulation.
 8. The formulationchamber for use with a parenteral delivery system according to claim 7,wherein the beneficial drug is housed in a means for storing andreleasing the drug.
 9. The formulation chamber for use with a parenteraldelivery system according to claim 7, wherein the beneficial drug iscontained in a mass transfer conductor for the drug.
 10. The formulationchamber for use with a parenteral delivery system according to claim 7,wherein the beneficial drug is an intravenously administrable drug. 11.The formulation chamber for use with a parenteral delivery systemaccording to claim 7, wherein the fluid that flows into the secondcompartment communicates with the beneficial drug that is housed in anon-toxic mass that releases the drug to the fluid.
 12. The formulationchamber for use with a parenteral delivery system according to claim 7,wherein the compartments are separated by a barrier that is permeable tothe passage of fluid.
 13. The formulation chamber for use with aparenteral delivery system according to claim 7, wherein the beneficialdrug is housed in a mass that is a drug delivery device.
 14. Theformulation chamber for use with a parenteral delivery system accordingto claim 7, wherein the drug is housed in a mass that is microporous.15. The formulation chamber for use with a parenteral delivery systemaccording to claim 7, wherein the beneficial drug is not in the directpath of fluid flow through the formulation chamber.
 16. An intravenousdelivery system for administering a drug formulation intravenously inwhich system the drug formlation is constituted in situ, said systemcomprising in combination:(a) a container of a pharmaceuticallyacceptable intravenously administrable fluid; and, (b) a formulationchamber in fluid communication with the container, said formulationchamber comprising:(1) a wall surrounding a space provided with a firstand second compartment; (2) fluid inlet means in fluid communicationwith the container for receiving fluid from the container and fluidoutlet means for letting fluid leave the chamber, said inlet and outletmeans communicating with the first compartment to provide a flow path;(3) means for permitting fluid to flow from the flow path into thesecond compartment; and, (4) an intravenously administrable solid drugcontained in the second compartment presented in a therapeuticallyeffective amount for producing a beneficial effect in an animal onintravenous therapy.
 17. The intravenous delivery system foradministering the drug formulation according to claim 16, wherein a dripchamber is in fluid communication with the container.
 18. Theintravenous delivery system for administering the drug formulationaccording to claim 16, wherein the drug is in a means for storing andreleasing the drug to fluid that enters the compartment, which meansmaintains its physical and chemical integrity in the presence of fluid.19. The intravenous delivery system for administering the drugformulation according to claim 16, wherein the compartments areseparated by a barrier.
 20. The intravenous delivery system foradministering the drug formulation according to claim 16, wherein thecompartments are separated by a barrier that permits the passage offluid.
 21. The intravenous delivery system for administering the drugformulation according to claim 16, wherein the compartments areseparated by a membrane and fluid passes through the pores of themembrane.
 22. A formulation chamber comprising:(a) housing meansdefining a first and second compartment within said housing means; (b)fluid inlet and outlet means in said housing means in fluidcommunication with said first compartment whereby a primary fluid flowpath is provided; (c) means in the formulation chamber for permitting apredetermined portion of the flow of fluid in said fluid flow path toflow through said second compartment; and, (d) said second compartmentadapted to retain a biologically beneficial drug in solid form, andwherein when the second compartment contains a therapeutically effectiveamount of drug and the formulation chamber is in use, fluid enters thesecond compartment and forms with the drug a fluid drug formulationuseful for intravenous therapy. .Iadd.
 23. A method for adding abeneficially parenterally administrable drug to a parenterallyacceptable fluid for forming a parenterally administrable fluidbeneficial drug formulation, which method comprises:(a) admitting theparenteral fluid into a formulation chamber, the formulation chambercomprising:(1) a wall surrounding a space provided with a first andsecond compartment therein; (2) fluid inlet and outlet meanscommunicating with the first compartment to provide a flow path; (3)means for permitting fluid to flow from the flow path through the secondcompartment; (4) a beneficial parenterally administrable drug in thesecond compartment; and, (b) adding the beneficial drug to the fluid bypermitting fluid to flow through the second compartment, wherein thebeneficial drug is added to the fluid thereby forming a parenterallyadministrable fluid beneficial drug formulation. .Iaddend. .Iadd.
 24. Aformulation chamber for use with a parenteral delivery system forformulating a parenterally administrable drug formulation comprising aparenterally administrable fluid and a parenterally administrable drug,the formulation chamber comprising:(a) a housing means defining a firstand second compartment therein; (b) fluid inlet and outlet means forconnecting said housing to a parenteral delivery system, said inlet andoutlet means communicating with the first compartment to provide a flowpath; (c) means for permitting fluid to flow from the flow path into thesecond compartment; (d) a beneficial parenterally administrable drughoused in the second compartment; and, (e) wherein, when the formulationchamber is in use with a parenteral delivery system, parenterallyadministrable fluid enters the formulation chamber and contacts theparenterally administrable drug for formulating a parenterallyadministrable drug fluid formulation. .Iaddend. .Iadd.25. An intravenousdelivery system for administering a drug formulation intravenously inwhich system the drug formulation is constituted in situ, said systemcomprising in combination: (a) a container of a pharmaceuticallyacceptable intravenously administrable fluid; and, (b) a formulationchamber in fluid communication with the container, said formulationchamber comprising:(1) a wall surrounding a space provided with a firstand second compartment; (2) fluid inlet means in fluid communicationwith the container for receiving fluid from the container and fluidoutlet means for letting fluid leave the chamber, said inlet and outletmeans communicating with the first compartment to provide a flow path;(3) means for permitting fluid to flow from the flow path into thesecond compartment; and, (4) an intravenously administrable drugcontained in the second compartment presented in a therapeuticallyeffective amount for producing a beneficial effect in an animal onintravenous therapy. .Iaddend. .Iadd.26. A formulation chambercomprising:(a) housing means defining a first and second compartmentwithin said housing means; (b) fluid inlet and outlet means in saidhousing means in fluid communication with said first compartment wherebya primary fluid flow path is provided; (c) means in the formulationchamber for permitting a predetermined portion of the flow of fluid insaid fluid flow path to flow through said second compartment; and, (d)said second compartment adapted to retain a biologically beneficial drugand wherein when the second compartment contains a therapeuticallyeffective amount of drug and the formulation chamber is in use, fluidenters the second compartment and forms with the drug a fluid drugformulation useful for intravenous therapy. .Iaddend.